Tomoko Akimoto

Novel transdermal drug penetration enhancer: synthesis and enhancing effect of alkyldisiloxane compounds containing glucopyranosyl group.

The syntheses of alkyldisiloxanes containing sugar moiety with various alkyl chain length were investigated, in order to develop a silicone-based transdermal penetration enhancer which was expected to show a low irritation to the skin. 1-Alkyl-3-beta-D-glucopyranosyl-1,1,3,3-tetramethyldisiloxanes (Glc-SiCs) were prepared by two-step hydrosilylations of 1-alkene and 1-allyl-beta-D-glucose tetraacetate with 1,1,3,3-tetramethyldisiloxane in the presence of bis(benzonitrile)platinum dichloride as the catalyst, followed by hydrolysis of the acetyl groups with sodium methoxide. The enhancing effect of Glc-SiCs on the percutaneous drug penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Antipyrine (ANP) and indomethacin (IND) were used as hydrophilic and hydrophobic model drugs, respectively, and the amount of drug permeating through the rat abdominal skin with or without Glc-SiCs was estimated by HPLC. As a result, Glc-SiCs exhibited a enhancing effect on the permeation of both drugs through the skin, which was influenced by the alkyl chain length of Glc-SiCs. In addition, it was suggested that a suitable balance of polarity would be necessary to appear the high enhancing effect, where Glc-SiCs with octyl and decyl groups exhibited the highest enhancing effect. From the determination of kinetic parameters in the drug permeation, it was also found that this enhancing effect was due to the increase of both partition and diffusion coefficients of drug permeation through the skin. By experiments to determine the amount of cholesterol extracted from the skin, the defatting effect would be one of the functions of Glc-SiCs which resulted in the high enhancing activity. Furthermore, according to the Draize test, it was confirmed that Glc-SiCs showed a low irritation to the skin.

Polymeric percutaneous drug penetration enhancer: Synthesis and enhancing property of PEG/PDMS block copolymer with a cationic end group

Poly(ethylene glycol)/polydimethylsiloxane (PEG/PDMS) block copolymers containing an ammonium moiety at one chain end with various molecular weights were prepared to develop a silicone-based polymeric transdermal penetration enhancer. As the precursor of the desired block copolymer, 3-chloropropyl-terminated PEG/PDMS block copolymers were prepared via an initiator method, i.e. the anionic ring-opening polymerization of hexamethylcyclotrisiloxane was carried out by initiating with silanolate anion derived from PEG-silanol, α-3-(dimethylhydroxysilyl)propyl-ω-methyl-PEG oligomer. The initiator, PEG-silanol, was obtained from α-allyl-PEG by hydrosilylation with dimethylethoxysilane, followed by hydrolysis of the ethoxysilyl group. The enhancing activity in the drug penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Indomethacin and antipyrine were used as hydrophobic and hydrophilic model drugs, respectively, and the amounts of drugs permeating through the rabbit abdominal skin were measured with or without these polymeric enhancers. These enhancers were very effective for the penetration of hydrophilic drug, but not for that of hydrophobic one. On the other hand, the enhancing activities were influenced by the chain length of PDMS and PEG components. A suitable balance between the hydrophobic PDMS segment and the hydrophilic PEG segment would exist for a high enhancing activity of drug penetration. It was also found that the enhancing activity was due to an increase of the partition coefficient of a drug into the stratum corneum, from the determination of kinetic parameters in the drug permeation.

Preparation of oligodimethylsiloxanes with sugar moiety at a terminal group as a transdermal penetration enhancer

Oligodimethylsiloxanes (ODMSs) containing glucose or cellobiose moiety at a terminal group were prepared to develop a silicone-based transdermal penetration enhancer. Glucopiranosyl-terminated ODMS was prepared by the hydrosilylation of hydrosilyl-terminated ODMS with 1-allyl-β-D-glucose tetraacetate followed by hydrolysis of the acetyl groups with sodium methoxide, to afford glucopiranosyl-terminated ODMS with a ether linkage between glucopiranosyl and ODMS components (GlcO-ODMS), and by the coupling reaction of iodopropyl-terminated ODMS with 2-(2,3,4,6-O-tetraacetyl-β-D-glucopyranosyl)thiopseudourea hydrobromide followed by the similar hydrolysis to afford glucopiranosyl-terminated ODMS with a thioether linkage (GlcS-ODMS). Cellobiosyl-terminated ODMS (Cell-ODMS) was also prepared by the similar procedure as GlcO-ODMS. The enhancing activity of GlcO-ODMS, GluS-ODMS and Cell-ODMS on the drug permeation through the rabbit abdominal skin was evaluated by in vitro experiments using a two-chamber diffusion cell and antipyrine as a model drug. The permeation of antipyrine through the skin was increased by the addition of GlcS-ODMS and GlcO-ODMS but not by Cell-ODMS.

Polymeric transdermal drug penetration enhancer. The enhancing effect of oligodimethylsiloxane containing a glucopyranosyl end group.

Oligodimethylsiloxanes (ODMSs) containing a beta-D-glucopyranosyl group at one chain end (Glc-ODMSs) with various molecular weights were prepared to develop a silicone-based polymeric transdermal penetration enhancer with a non-ionic polar end group. Glc-ODMSs were prepared by hydrosilylation of hydrosilyl-terminated ODMS with 1-allyl-beta-D-glucose tetraacetate in the presence of bis(benzonitrile)platinum dichloride as the catalyst, followed by hydrolysis of the acetyl groups with sodium methoxide. The enhancing effect in the drug penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Antipyrine was used as a model drug, and the amount of drug permeating through the rat abdominal skin with or without Glc-ODMS was determined by HPLC. These enhancers were effective for the penetration of antipyrine. On the other hand, the enhancing effects were influenced by the concentration of Glc-ODMS coexisted regardless of its ODMS chain length. The enhancing effect was also observed by the pretreatment of the skin with Glc-ODMS before the drug permeation, the results of which suggested that the induction periods to appear the enhancing effects were different between Glc-ODMSs with the short and the long ODMS chain lengths. Furthermore, according to the Draize test, Glc-ODMSs exhibited no irritation to the skin regardless of the ODMS chain length.

Preparation of Polydimethylsiloxanes Containing Cationic or Anionic Group at the Chain End and Their Transdermal Penetration Enhancement.

片末端にクロロメチルフェネチル基を有するポリジメチルシロキサン (PDMS-BzCl) を用い, 三級アミンを用いた四級化反応によりカチオン基を片末端に有するPDMSを合成した. また, カルボニル挿入反応及び加水分解により, アニオン基を片末端に有するPDMSを合成した. 得られたポリマーの経皮吸収促進効果をウサギ腹部剥離皮膚を用いたin vitro薬物透過実験により評価した. いずれのポリマーも薬物の皮膚吸収を促進し, その効果はカチオン性PDMSでは重合度が増大するに従って増加し, 平均重合度が12付近で最大値を示した. 一方, アニオン性PDMSでは重合度が低いほど促進効果は大きかった. 薬物の皮膚吸収過程における透過, 拡散, 分配の各係数を算出した結果, これらのポリマーは薬物の基剤から皮膚への分配のみを高めることによって効果を発現しており, 低分子量促進剤とは促進効果発現機序が異なることが示唆された.